Prodrug Strategies for HCV Nucleoside Lead Development

描述（由申请人提供）：据估计，全世界有超过2亿人慢性感染HCV，因此有发生危及生命的肝病的风险。目前唯一可用的治疗方法是聚乙二醇干扰素和核苷类似物利巴韦林的联合治疗。不幸的是，这种组合在不到一半的治疗患者中表现出有限的功效，并且受到治疗限制性副作用和毒性的困扰。此外，越来越多的报告显示，在临床试验中对研究性小分子的耐药性正在出现，这强调了对新的和更有效的治疗方法的需求。许多修饰的核苷已经显示出作为HCV聚合酶抑制剂的有效活性，然而，无效递送、毒性、不稳定性和/或不良药代动力学的问题使得许多有希望的类似物不适合，因此许多研究人员转向在核苷的5 '-OH上使用前药或“掩蔽”基团来克服这些问题。本申请的重点是一系列扩展的嘌呤核苷类似物，我们预计将表现出有效的活性对HCV RNA依赖的RNA聚合酶（RdRp）NS 5 B由于一些战略性设计的结构特征。这种应用的影响是双重的;第一，医学发现最终可能产生全球影响，因为迫切需要更有效的HCV治疗。此外，基本的科学影响还包括扩大我们对特异性靶向HCV NS 5 B聚合酶以及肝细胞的药物输送方法的了解范围。此外，新的和改进的核苷类似物的合成方法将进行调查。因此，这项工作的科学影响不仅仅是全球健康研究，而且还将为学生提供有价值的培训，因为合成有机和药物输送方法以及获得的有关聚合酶的信息将高度适用于广泛的疾病。

DESCRIPTION (provided by applicant): More than 200 million people worldwide are estimated to be chronically infected with HCV and as a result, at risk for developing life-threatening liver diseases. The only treatment currently available is a combination therapy of pegylated interferon and Ribavirin, a nucleoside analogue. Unfortunately this combination has exhibited limited efficacy in less than half of treated patients, as well as being plagued with treatment- limiting side effects and toxicity. In addition, increasing reports of drug resistance to investigational small molecules in clinical trials are emerging, underscoring the need for new and more effective treatments. A number of modified nucleosides have exhibited potent activity as inhibitors of HCV polymerase, however problems with ineffective delivery, toxicity, instability and/or poor pharmacokinetics have rendered many promising analogues unsuitable, thus many researchers are turning to use of a prodrug, or "masking" group, on the 5'-OH of the nucleoside, to overcome these problems. This application focuses on a series of expanded purine nucleoside analogues that we anticipate will exhibit potent activity against the HCV RNA-dependent RNA polymerase (RdRp) NS5B due to a number of strategically designed structural features. The impact of this application is two-fold; one, the medicinal discoveries could ultimately have a global impact, as more effective HCV treatments are desperately needed. In addition, the basic scientific impacts include expanding the breadth of our knowledge of drug delivery methods for specific targeting of the HCV NS5B polymerase, as well as liver cells. In addition, new and improved methodology for nucleoside analogue synthesis will be investigated. As such, the scientific impact of this work goes beyond just global health research, but will also provide valuable training for students, as the synthetic organic and drug delivery methodologies and the information obtained about polymerases will be highly applicable across a broad scope of diseases.